N-substituted-norapomorphines

ABSTRACT

Certain N-substituted-norapo-morphines useful as emetics, hypotensives, and CNS stimulants.

United States Patent 91 Archer [52] U.S. Cl....260/289 R, 260/283 CN,260/283 SY, 260/285, 260/289 A, 260/999, 424/260 [51] Int. Cl. ..C07d43/28 [58] Field of Search ..260/285, 289 R [56] References Cited OTHERPUBLICATIONS Weisbach et al., J. Med. Chem., Vol. 6, pp. 91 to 97(1963).

[451 Feb. 20, 1973' Bentley, The Isoquinoline Alkaloids, Pergamon Press,New York, 1965, pp. 66, 67, 144 and 145 QD421 B3i.

Primary Examiner-Leland A. Sabastian Attorney-Elem J. Lawson, B. WoodrowWyatt, Thomas L. Johnson, Robert K. Bair, R. Clifford Bourgeois, WilliamG. Webb and Roger T. Wolfe [5 7 ABSTRACT CertainN-substituted-norapo-morphines useful as emetics, hypotensives, and CNSstimulants.

7 Claims, No Drawings N-SUBSTITUTED-NORAPOMORPI-IINES This inventionrelates to new N-substitutednorapomorphines having the formula where Ris lower-alkyl of from two to four carbon atoms, 2-chlorobutyl,cyclopropyl, cyclopropylmethyl, or Z-phenylethyl. When R is lower-alkylof from two to four carbon atoms, the lower-alkyl group can be straightor branched, and thus R as lower-alkyl represents, inter alia, ethyl,n-propyl, isopropyl, n-butyl, and the like.

The compounds of formula I above have emetic activity and are thususeful in medicine, for example, in cases of acute poisoning, alcoholicintoxication, acute indigestion, or in other cases where it is necessaryor desirable to empty the stomach contents rapidly, and apomorphine (I:R is CH is a well-known emetic agent used for this purpose. Thecompounds of the present invention, especially N-ethyl-andN-n-propylnorapomorphine, however, have been found to be substantiallymore active as emetic agents than apomorphine, while their toxicity isof approximately the same order of magnitude as the latter. The instantcompounds therefore possess a greater therapeutic ratio, i.e., the ratioof the toxic dose to the effective dose, in comparison with apomorphine.

The instant compounds also have been found to have hypotensive and CNSstimulant activities further indicating their usefulness as hypotensiveagents and CNS stimulants, and again the N-ethyl-andN-n-propylnorapomorphine have substantially greater hypotensive activitythan the known apomorphine.

The compounds of formula 1 above are prepared by acid-catalyzedrearrangement of an N-substituted-no'rmorphine according to theequation:

l t HO II I where R has the meanings given above. A preferred acidcatalyst is phosphoric acid/anhydrous hydrogen place as described above,but the cyclopropyl ring is I also opened by the attack of a molecule ofhydrogen chloride.

The compounds of formula I where R is cyclopropylmethyl are thereforeadvantageously prepared by alkali metal aluminum hydride reduction ofthe corresponding N-cyclopropylcarbonylnorapomorphine (I: R is C I-I CO)at a temperature between about 0 C. and about 65 C. in an organicsolvent inert under the conditions of the reaction, for example, etheror tetrahydrofuran. It is preferred to use lithium aluminum hydride inrefluxing tetrahydrofuran.

The compounds of formula I were R is cyclopropylmethyl can also beprepared by rearrangement of N- cyclopropylmethylnormorphine, asdescribed above, in the absence of hydrogen chloride, under whichconditions the cyclopropylmethyl' group survives the rearrangementwithout ring opening.

The N-cyclopropylcarbonylnorapomorphine is in turn prepared by reactingnorapomorphine (I: R is H) with a cyclopropylcarbonyl halide in anorganic solvent inert under the conditions of the reaction, for example,benzene, toluene, xylene, and the like, and in the presence of anacid-acceptor, for example, tri-lower-alkylamines or alkali metalcarbonates or bicarbonates, the purpose of which is to take up thehydrogen halide split out during the course of the reaction.

The N-substituted-normorphines of formula II are in I turn prepared byalkylation of normorphine with an appropriate alkyl halide, RX, where Xis halogen, and R has the meanings .given above. The reaction isrepresented by the equation:

HO HO The reaction is preferably carried out in the presence of anacid-acceptor and in an organic solvent inert under the conditions ofthe reaction, for example, methanol, ethanol, benzene, toluene,dimethylformamide, and the like; The purpose of the acid-acceptor is totake up the hydrogen halide which is split out during the course of thereaction and can be any basic substance which forms water-soluble saltseasily separable from the reaction mixture. Suitable acid-acceptors arealkali metal hydroxides, for example sodium and potassium hydroxides,and alkali metal carbonates or bicarbonates, for example sodium orpotassium carbonates or bicarbonates.

Alternatively the N-substituted-normorphines of formula II, required asintermediates for the preparation of the compounds of formula I, areprepared by reductive alkylation of normorphine (formula III). That is,normorphine is reacted with an aliphatic aldehyde under acidicconditions in the presence of a reducing agent. It is preferred to carryout the reaction in an organic solvent inert under the conditions of thereaction, for example, methanol, ethanol, .isopropanol, and the like, inthe presence of acetic acid. A preferred reducing agent is sodiumborohydride.

where R represents lower-alkyl and Ii has the meanings given above. Thislatter procedure is described and claimed in Neumeyer application, Ser.No. 638,184, filed concurrently herewith.

When the compounds of formula I are prepared by the above-describedprocedure from a racemic l-(2- amino-3,4-di-lower-alkoxybenzyl)-2-substituted- 1,2,3,4-tetrahydroisoquinoline,the product produced is isolated as a racemic mixture. On the otherhand,

when the compounds of formula I are prepared by acidcatalyzedrearrangement, as described above, of an N- substituted-normorphineobtained from natural sources and thus optically active, the products offormula I produced in the reaction retain the optical activity.

The compounds of formula ,I are basic substances which interact with oneequivalent of an organic or inorganic acid to form the correspondingacid-addition salts. These acid-addition salts and the free bases ofcourse have the common structural entity represented by structuralformula I. The acid-addition salts are the full equivalents of the freebase form, and the new compounds of this invention include both the freebases and the acid-addition salts thereof. The novel feature of thecompounds of the invention thus resides in the concept of the bases andthe cationic forms of the new N-substituted-norapomorphines and not inany particular acid moiety or acid anion associated with the salt formganic group therein), an organo-metallic acid as exemplified by organicmonoand poly-ca'rboxylic acids such as found, for example, in BeilsteinsOrganische Chemie, 4th Ed., Volumes III, IV, IX, X, XIV, XVII, XIX, XXI,XXII, and XXV; organic monoand polysulfonic and sulfinic acids such asfound,.for example, in Beilstein Volumes VI, XI, XVI, and XXII; organicphosphonic and phosphinic acids such as found, for example, in BeilsteinVolumes XI and XVI; organic acids of arsenic and antimony such as found,for example, in Beilstein Volume XVI; organic heterocyclic carboxylic,sulfonic, and sulfinic acids such as found, for example, in BeilsteinVolumes XVIII, XXII, and XXV; acidic ion-exchange resins; and inorganicacids of any acid-forming element or combination of elements such asfound in Mellor, Comprehensive Treatise on Inorganic and TheoreticalChemistry, Longmans Green and Co., New York, N.Y., Volumes I-XVI. Inaddition, other salt-forming compounds which are acidic in theirchemical properties but which are not generally considered as acids inthe same sense as carboxylic or sulfonic acids are also considered to beamong the numerous acids which can be used to prepare acid-additionsalts of the compounds of the invention. Thus there are alsocomprehended acidic phenolic compounds such as found, for example, inVolume VI of Beilstein, acidic compounds having activated or acidichydrogen atoms, as for example, picrolonic acid, or barbituric acidderivatives having an acidic proton such as found, for example, in Coxet al., Medicinal Chemistry, Vol. IV, John Wiley and Sons, Inc., NewYork, N.Y. (1959). Also comprehended as salt-forming agents areso-called Lewis acids which lack a pair of electrons in the outerelectron shell and react with basic compounds 'iia'viigan unshared pairof electrons to form salts, for example, boron trifluoride.

Representative acids for the formation of the acidaddition salts includeformic acid, acetic acid, isobu-- tyric acid, alpha-mercaptopropionicacid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid,succinamic acid, glutamic acid, tartaric acid, oxalic acid, pyromucicacid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharicacid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylicacid, acetylsalicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid,pamoic acid, chloic acid, 2- pyridinecarboxylic acid,3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, saccharin, butylarsonic acid, methanephosphonicacid, acidic ionexchange resins, hydrofluoric acid, hydrochloric acid,hydrobromic acid, hydriodic acid, perchloric acid,

nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid,phosphotungstic acid, molybdic acid, arsenic acid, and the like.

The acid-addition salts are prepared in conventional fashion, forinstance either by direct mixing of the acid and the base or, when thisis not appropriate, by dissolving the acid and the base separately in asuitable solvent and mixing the two solutions, or by dissolving both theacid and the base together in a solvent. The resulting acid-additionsalt is isolated by filtration, if it is insoluble in the reactionmedium, or by evaporation of the reaction medium to leave theacid-addition salt as a residue.

The new bases of formula I and the acid-addition salts thereof havepharmacodynamic properties and are particularly useful as emetics,hypotensives, and C.N.S. stimulants, as described above.

The acid-addition salts of the bases of formula I are useful not only asemetics, hypotensives, and C.N.S. stimulants asabove indicated, but arealso useful as characterizing or identifying derivatives of the freebases and in isolation or purification procedures. Moreover, theacid-addition salts react with strong bases, such as alkali metalhydroxides, to regenerate the free bases, and accordingly all of thesalts, regardless of considerations of solubility, toxicity, physicalform, or the like of a particular species of acid-addition salt, areuseful for the purposes of the invention since they are sources of thefree bases.

It will be appreciated from the above that if one or more of thecharacteristics, such as solubility, molecular weight, physicalappearance, toxicity, or the like, of a given acid-addition salt renderit less suitable or unsuitable for the particular desired purpose, asfor example, use as an emetic or hypotensive agent or in an isolation orpurification procedure, or the like, the acid-addition salt can beconverted to the free base and then to another, more suitableacid-addition salt, for instance a pharmaceutically-acceptable salt whena pharmaceutical use is involved.

The following examples will further illustrate the invention without thelatter being limited thereto:

EXAMPLE 1 l-N Cyanonorheroin To a stirred solution of 22 g. (0.21 mole)of cyanogen bromide in 400 ml. of chloroform was added a solution of65.4 g. (0.177 mole) of heroin in 300 ml. of chloroform at roomtemperature. The solution was then stirred at room temperature for 1%hours, refluxed for 3 hours, allowed to stand overnight, and decantedfrom a small amount of insoluble material. The supernatant liquid wasevaporated to dryness in vacuo, and the residual solid was trituratedwith methanol and collected giving 44.1 g. of l-N-cyanonorheroin, m.p.242246C. (uncorr.).

EXAMPLE 2 l-Normorphine (111) A solution of 15:9 g. (0.042 mole) ofl-N-cyanonorheroin in 72 ml. of concentrated hydrochloric acid washeated on a steam bath for five minutes, diluted with 570 ml. of water,and warmed on a steam bath for an additional seven hours with stirring.The clear solution was then filtered, concentrated to a volume of about200 ml., cooled, and basified with concentrated ammonium hydroxide. Thesolid which separated was collected, washed with ice water, and driedgiving 10.8 g. of normorphine.

EXAMPLE 3 l-N-Ethylnormorphine (II: R is C H A mixture of 2.5 ml. ofacetaldehyde, 2.5 g. (0.009 mole) of l-normorphine, 7.5 ml. of glacialacetic acid, 40 ml. of ethanol, 14 ml. of water, and 1.2 g. of anhydroussodium acetate was treated portion-wise at 2 C. with 0.9 g. (0.024 mole)of sodium borohydride. Second portions of 2.5 ml. of acetaldehyde and0.9 g. of sodium borohydride were added and the reaction mixture allowedto warm to room temperature. Excess borohydride was decomposed byaddition of 25 ml. of concentrated hydrochloric acid, the mixture wasextracted with three 50 ml. portions of ether, and the aqueous phase wasbasified to pH 9 with concentrated ammonium hydroxide. Extraction of theaqueous phase with methylene dichloride, drying the extracts over sodiumsulfate, and evaporation of the extracts to dryness afforded 2.2 g. ofl-N-ethylnormorphine, m.p. 200-202C.

Anal. Calcd. for c,,ii,,No,= C, 72.21; H, 7.07; N,

4.68 Found: C, 72.03; H, 7.11: N, 4.61.

EXAMPLE 4 H, N,

l-N-Ethylnorapomorphine Hydrochloride (I: R is am) A solution of 5.1 g.(0.017 mole) of l-N-ethylnormorphine in ml. of percent phosphoric acidwas heated at -l53 C. for 1 hour while anhydrous hydrogen chloride waspassed through the solution. The cooled reaction mixture was poured into85 ml. of saturated aqueous sodium chloride, and the gummy precipitatewhich separated was triturated with cold water, dissolved in 75 ml. ofwarm water, and the resulting solution treated with a solution of 12 g.of sodium sulfite in 60 ml. of water. The cream-colored solid thatseparated was extracted with methylene dichloride and chloroform. Theextracts were set aside, and the residue was extracted with boilingethanol. The ethanol extract was then acidified with a solution ofhydrogen chloride in ether and diluted with ether to precipitate thehydrochloride salt, which was collected and dried giving 280 mg. ofcolorless needles consisting of l-N-ethylnorapomorphine hydrochloride,m.p. 280-282 C.

Anal. Calcd. for c,,H,,No,Hcl; C, 68.03; H, 6.34;

Cl, 11.15; N, 4.41 Found: C, 67.52; H, 6.18; Cl, 10.90; N, 4.29

In emetic activity studies in dogs, l-N-ethylnorapomorphine was found tohave a minimum effective dose (MED) on intravenous (i.v.) administrationof 0.00025 mg./kg. ln'the same tests with l-apomorphine, the latter wasfound to have an MED of 0.012 mg./kg. (i.v.).

ln hypotensive activity studies in the anesthetized cat,l-N-ethylnorapomorphine was-found to have an MED on intravenousadministration of 0.0002 mg./kg. In the same tests with l-apomorphine,the latter was found to have an MED of 0.001 mg./kg. (i.v.).-

The LD the dose lethal to 50 percent of the test animals, on intravenousadministration in mice of l-N- ethylnorapomorphine and l-apomorphinewere found to be 45 mg./kg. and 71 mg./kg., respectively.

EXAMPLE l-N-n-Propylnormorphine (II: R is nC H-,)

A mixture of 2.7 g. (0.01 mole) of l-normorphine, 2 g. (0.024 mole) ofsodium bicarbonate, and 1 ml. (0.01 mole) of n-propyl iodide in 25 ml.of dimethylformamide was heated on a steam bath for several hours,evaporated essentially to dryness under reduced pressure, the residuetriturated with water, and the resulting solid was collected and driedgiving 2.4 g. of l-N-npropylnormorphine.

l-N-n-Propylnormorphine was also prepared by reductive alkylationaccording to the following procedure:

25 g. (0.093 mole) of l-normorphine was dissolved in a mixture of 75 ml.of glacial acetic acid, 400 ml. of acetone, 160 ml. of water, and 12 g.of anhydrous sodium acetate. To the resulting mixture was then added 25ml. (0.35 mole) of propionaldehyde, and the solution was cooled to -20C. The mixture was then treated over a period of about 20 minutes whilestirring at about 3 C. with 9 g. (0.24 mole) of sodium borohydride.Second portions of 25 ml. of propionaldehyde and 9 g. of sodiumborohydride were then added, and

thereactiori mixture sfirredandallowd to warmto room temperature. Themixture was diluted with 250 ml. of water, rendered strongly acidic withconcen- C. (uncorn), which after several recrystallizations from ethanolgave m.p. 233-235 C. (uncorn);

' [a],;-- 135 C. (0.53 percent ethanol).

EXAMPLE 6 1-N-n-Propylnorapomorphine Hydrochloride (I: R is n'-C H Asolution of 15 g. (0.048 mole) of l-N-n-propylnormorphine in 85 ml. of85 percent phosphoric acid was heated in an oil bath at an internaltemperature of 145-150 C. for 1 hour while passing a stream of anhydroushydrogen chloride through the solution. The

' mixture was then cooled, diluted with 30 ml. of water,

and the solution saturated with solid sodium chloride to cause theseparation of an amorphous solid. The latter was collected and dissolvedin a minimum amount of water, and the solution treated with 1.5 g. ofsodium sulfite. The mixture was then extracted with ether, and anhydroushydrogen chloride gas was bubbled through the combined extracts. Theoily solid which separated In hypotensive activity studies in theanesthetized cat, l-N-n-propylnorapomorphine was found to have an MED onintravenous administration of 0.000075, mgJkg.

The LD the dose lethal to 50 percent of the test animals, on intravenousadministration in mice of l-N- n-propylnorapomorphine was found to be79.0 mg./kg.

EXAMPLE 7 d,1-N-n-Propylnorapomorphine Hydriodide (I: R is nC Hl-(2-Nitro-3 ,4-dimethoxybenzyl)-2-propyl-1,2,3 ,4-tetrahydroisoquinoline (1.5 g., 0.004 mole) was dissolved in 50 ml. ofmethanol and reduced with hydrogen over 250 ml. of 5 percentpalladium-on-charcoal. When reduction was complete, the solution wasfiltered from the catalyst and evaporated to dryness giving an oilyresidue which was distilled in vacuo to give 0.95 g. ofl-(2-amino-3,4-dimethoxybenzyl)-2- propyl-l,2,3,4-tetrahydroisoquinoline as a viscous pale yellowoil, b.p.182C./0.l mm., n 1.5761.

The latter (5.10 g., 0.015 mole), dissolved in IN sulphuric acid, wastreated dropwise at 2 C. with an aqueous solution of sodium nitriteuntil a positive test for nitrous acid was obtained on starch-iodidepaper. The solution was then stirred for an additional fifteen minutesat room temperature, treated with 1.0' g. of

copper powder, stirred under nitrogen, and filtered. The filtrate wasthen treated with 1.0 g. of zinc dust and 10 ml. of 1N sulphuric acid,heated on a steam bath for 15 minutes, and filtered. The filtrate wasbasitied with ammonium hydroxide, extracted with ether, and the combinedether extracts dried, and taken to dryness. The residual oil, consistingof 1.85 g. of d,1-N-npropylnorapomorphine dimethyl ether, was convertedto its hydriodide salt, m.p. 245 C.

The latter was dissolved in about 4 ml. of 57 percent hydriodic acid,treated with about 3 ml. of acetic anhydride, and the resulting mixtureheated under reflux for 1 hour. The reaction mixture was cooled to roomtemperature, diluted with ether and the solid which separated wascollected and recrystallized from ethanol/ether to gived,1-N-n-propyl-norapomorphine hydriodide, m.p. 278 C. (dec.).

In emetic activity studies in dogs d,1-N-n-propylnorapomorphine wasfound to have a minimum effective dose (MED) on intravenousadministration of 0.00125 mgJkg. In the same tests with d,1-apomor'-'phine, the latter was found to have an MED of 0.025

mg./kg. (i.v.).

The LD the dose lethal to 50 percent of the test animals, on intravenousadministration in mice for both d,l-N-n-propylnorapomorphine andapomorphine was foundto be 10.0 mg./kg.

EXAMPLE 8 dehyde. The resulting solution was cooled to 0 C., and v 8 g.(0.22 mole) of sodium borohydride was added portion-wise over a periodof about an hour and a half while maintaining the reaction temperatureat 4 to 8 C. An additional 12 ml. of n-butyraldehyde was added afterabout half of the borohydride had been added. The mixture was stirredfor an additional 30 minutes following addition of the borohydride, andthe reaction mixture was then treated with 8 ml. of concentratedhydrochloric acid in 400 ml. of water. The reaction mixture wasextracted with ether to remove excess aldehyde, adjusted to pH 9 byaddition of aqueous ammonium hydroxide, and the resulting mixtureextracted with methylene dichloride. Drying of the methylene dichlorideextracts over sodium sulfate and evaporation to dryness gave asemi-solid which, after trituration with ether, afforded 6.4 g. ofl-N-n-butylnormorphine as a buff-colored solid, m.p. 195-198 C. (dec.),[a] 1 15 (1 percent, ethanol).

EXAMPLE 9 l-N-n-Butylnorapomorphine Hydrochloride (l: R is nC H Asuspension of g. (0.015 mole) of l-N-n-butylnormorphine in 28 ml. of 85percent phosphoric acid was heated in an oil bath at 145l50 C. while astream of anhydrous hydrogen chloride was passed through the mixture.The passage of hydrogen chloride was continued for one hour after allsuspended solid had dissolved, and the cooled reaction mixture waspoured into 95 ml. of water. The product was salted out by addition of10 g. of solid sodium chloride. After isolation of the crude product, itwas converted to the free base form, extracted with ether, and convertedto the hydrochloride salt. There was thus obtained 1.2 g. ofl-N-n-butylnorapomorphine hydrochloride as a light tan powder, m.p.175-190 C.

Anal. Calcd. for C H NO .HCl: C, 69.43; H, 6.94;

Cl, 10.28; N, 4.05 Found: C, 69.27; H, 7.04; Cl, 10.34; N, 4.09.

.EXAMPLE l0 1-N-(2-Chlorobutyl)norapomorphine Hydrochloride (I: R is CHCl-1 CHClCH A suspension of 6 g. (0.018 mole) ofl-N-ncyclopropyl-normorphine in 75 ml. of 85 percent phosphoric acid washeated at 150 C. for 30 minutes while bubbling a stream of anhydroushydrogen chloride through the mixture. The resulting solution was heatedfor an additional hour at 150 C., cooled, and poured into 150 ml. 'ofsaturated aqueous sodium chloride. The resin which separated wascollected, washed with water, dissolved in 500 ml. of water at 60 C.,filtered, and the filtrate treated with a solution of 30 g. of sodiumsulfite in 200 ml. of water. The resulting mixture was cooled to 0 C.,extracted with three 250 ml. portions of chloroform, and the combinedchloroform extracts diluted with an equal volume of ether, and driedover sodium sulfate. The dried organic solution was treated with 100 ml.of saturated ethereal hydrogen chloride and evaporated to dryness invacuo giving 1.1 g. of an amorphous powder, m.p. 160-l80 C. (dec.). Thelatter was recrystallized once from an absolute ethanol/ether mixtureand once from acetonitrile giving 121 mg. of1-N-(2-chlorobutyl)norapomorphine hydrochloride, m.p. 170-175 C.

Anal. Calcd. for c,,,H,,c1No,Hc1;c, 63.16; H, 6.09;

Cl, 18.64; N, 3.68 Found: C, 62.55; H, 6.28; Cl, 17.55; N, 3.69.

10 EXAMPLE 11 l-N-lsopropylnormorphine [II: R is (CH CH] is prepared byreacting l-normorphine with isopropyl bromide in the presence of sodiumbicarbonate in dimethylformamide following the manipulative proceduredescribed above in Example 5.

EXAMPLE l2 1-N-Isopropylnorapomorphine [1: R is (CH CH] is prepared byrearrangement of l-N-isopropylnormorphine in 85 percent phosphoric acidin the presence of anhydrous hydrogen chloride using the manipulativeprocedure described above in EXAMPLES 4 and 6.

EXAMPLE 13 EXAMPLE l4 1-N-Cyclopropylmethylnorapomorphine (l: C l-lCl-l) Reduction of 1-N-cyclopropylcarbonylnorapomorphine with lithiumaluminum hydride in tetrahydrofuran, and isolation of the product'from abasic medium after decomposition of excess hydride with water, af-

fords l-N-cyclopropylmethylnorapomorphine.

EXAMPLE l5 l-N-(Z-Phenylethyl)normorphine (II: R is C H,,,CH 2)Normorphine (12 g., 0.045 mole) was dissolved in a mixture of 200 ml. ofacetone, 34 ml. of glacial acetic acid, ml.'of water, and 6 g. ofanhydrous sodium acetate. To the mixture was added 5 ml. ofphenylacetaldehyde, and the mixture was stirred at 05 C. while adding 4g. (0.108 mole) of sodium borohydride over a thirty minute period.Second portions of 5 m1. of phenylacetaldehyde and 4 g. of sodiumborohydride were similarly added, and the reaction mixture was thenallowed to warm slowly to room temperature. The mixture was then dilutedwith 200 ml. of water, acidified carefully with excess concentratedhydrochloric acid, and extracted with three 200 ml. portions of ether.The aqueous raftinate was then basified by the addition of excessconcentrated ammonium hydroxide, and the solid material which separatedwas collected, washed with water and dried to give 10 g. of crudeproduct, m.p. 247-250 C. Recrystallization of this material from anethanol/chloroform mixture afforded l-N-(2-phenylethyl)normorphine as acolorless solid, mp 248-250 C.

Anal. Calcd. for C ,,H N0 C,76.00; H,6.93; N,3.85

Found:C,75.97; H,6.84;N,3.69.

EXAMPLE l6 l-N-(2-Phenylethyl)norapomorphine hydrochloride (1: R is C HCH CH A suspension of 8 g. (0.022 mole) of1-N-(2-phenylethyl)normorphine is 80 ml. of percent phosphoric acid washeated to C. over a 30 minute period Ris while anhydrous hydrogenchloride was passed through the mixture and was then maintained at 150C. for one hour while hydrogen chloride was continuously bubbledthrough'the mixture. The solution was then cooled and poured slowly withstirring into 175 ml. of saturated aqueous sodium chloride, and theprecipitate that separated was collected, suspended in 50 ml. of water,refiltered, and dissolved in a mixture of 400 ml. of water and 200 ml.of ethanol containing g. of sodium sulfite at 60 C. Extraction of thesolution with two 250 ml. portions of chloroform, dilution of thecombined extracts with one liter of ether, drying the extracts overmagnesium sulfate, and evaporation of the solvent afforded a dark brownsolid. The latter was dissolved in 600 ml. of water at 60 C., thesolution filtered through glass wool, and the filtrate treated with 20g. of sodium sulfite. The cream-colored solid which separated wascollected, dissolved in ether and the resulting solution treated with 50ml. of ethereal hydrogen chloride which caused the separation of l.5 g.of l-N-(2-phenylethyl )norapomorphine hydrochloride as a light tansolid, mp. l70-l 80 C.

Anal. Calcd. for C, H NO .HCl: C,73.16; l-l,6.l4;

Cl,9.00; N,3.56 Found: C,72.44; H,6.27; Cl,9.l8; N,3.82. I claim: 1. Acompound having the formula wherein R is lower-alkyl containing fromtwoto four carbon atoms; 2-chlorobutyl; cyclopropyl; cyclopropylmethyl; orZ-phenylethyl.

2. l-N-Ethylnorapomorphine according to claim 1 wherein R is C l-i 3.l-N-n-Propylnorapomorphine according to claim 1 wherein R is nC H,.

4. d,1-N-n-Propylnorapomorphine according to claim 1 wherein R is nC H,.

5. l-N-n-Butylnorapomorphine according to claim 1 wherein R is n-C H 6.l-N-(2-Chlorobutyl)norapomorphine according to claim 1 wherein R is Cl-lC h CHClCH 7. 1-N-(2-Phenylethyl)norapofnorphine according to claim 1wherein R is C l-l Cl-l Cl-fi.

1. A compound having the formula
 2. 1-N-Ethylnorapomorphine according toclaim 1 wherein R is C2H5.
 3. 1-N-n-Propylnorapomorphine according toclaim 1 wherein R is n-C3H7.
 4. d,1-N-n-Propylnorapomorphine accordingto claim 1 wherein R is n-C3H7.
 5. 1-N-n-Butylnorapomorphine accordingto claim 1 wherein R is n-C4H9.
 6. 1-N-(2-Chlorobutyl)norapomorphineaccording to claim 1 wherein R is CH3Ch2CHClCH2.